Resistances to drugs are the main reason why breast cancer cannot effectively be fought in many patients. Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now succeeded in restoring the sensitivity of resistant breast cancer cells to tamoxifen using a tiny RNA molecule. These snippets of RNA repress production of a protein that enhances cancer growth. In tissue samples of breast tumours, the investigators found clues that they also play a clinically relevant role.
Many breast cancer patients are treated with a drug called tamoxifen. The substance blocks the effect of oestrogen and thus suppresses the growth signals of this hormone in cancer cells. When resistance to the drug develops, tumour cells change their growth program: They change their behaviour and shape, become more mobile and also adopt the ability to invade surrounding tissue. Scientists working with PD (Associate Professor) Dr. Stefan Wiemann of the German Cancer Research Center (DKFZ) have now also observed these changes in tamoxifen resistant breast cancer cells.
‘Resistances to drugs are the main reason why therapies fail and disease progresses in many cancers,’ Wiemann explains. ‘We want to understand what goes on in the cells when this happens so we can develop better therapies in the future.’ Wiemann’s co-worker, Dr. Özgür Sahin, suspects that tiny pieces of RNA known as microRNAs play a role in resistance development. ‘These minuscule RNA snippets control many cellular processes by attaching themselves to target gene transcripts and thus repressing protein production.’
By treating breast cancer cells in vitro with regular doses of tamoxifen, Sahin’s team induced resistance of these cells to the drug. As resistance developed, the cancer cells switched to the development program that makes them grow even more invasively and more malignantly. Checking the complete spectrum of microRNAs in the resistant tumour cells, the investigators noticed that production of microRNA 375 was more strongly reduced than others. When they boosted the production of microRNA 375, the cells started responding again to tamoxifen and switched back to their normal growth program. ‘This strongly suggests that a lack of microRNA 375 both increases malignancy and contributes to resistance development,’ says Özgür Sahin.
If microRNA 375 levels are low, breast cancer cells increase the production of metadherin. Apparently, microRNA 375 suppresses the production of this cancer-promoting protein in healthy cells. In patients receiving tamoxifen therapy the team found that high metadherin levels in the cancer cells go along with a high risk of recurrence. This suggests that microRNA 375 and metadherin are involved in the development of resistance to tamoxifen.
‘The analysis of microRNAs in breast cancer has put us on the track of metadherin. We will possibly be able to specifically influence the cancer-promoting properties of this protein in the future,’ says Wiemann describing the goal of further research. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Researchers in the University of Leicester’s Department of Cell Physiology and Pharmacology have identified a cellular mechanism that could underlie the development of tinnitus following exposure to loud noises. The discovery could lead to novel tinnitus treatments, and investigations into potential drugs to prevent tinnitus are currently underway.
Tinnitus is a sensation of phantom sounds, usually ringing or buzzing, heard in the ears when no external noise is present. It commonly develops after exposure to loud noises (acoustic over-exposure), and scientists have speculated that it results from damage to nerve cells connected to the ears.
Although hearing loss and tinnitus affect around ten percent of the population, there are currently no drugs available to treat or prevent tinnitus.
University of Leicester researcher Dr Martine Hamann, who led the study said: ‘We need to know the implications of acoustic over exposure, not only in terms of hearing loss but also what’s happening in the brain and central nervous system. It’s believed that tinnitus results from changes in excitability in cells in the brain – cells become more reactive, in this case more reactive to an unknown sound.’
Dr Hamann and her team, including PhD student Nadia Pilati, looked at cells in an area of the brain called the dorsal cochlear nucleus – the relay carrying signals from nerve cells in the ear to the parts of the brain that decode and make sense of sounds. Following exposure to loud noises, some of the nerve cells (neurons) in the dorsal cochlear nucleus start to fire erratically, and this uncontrolled activity eventually leads to tinnitus.
Dr Hamann said ‘We showed that exposure to loud sound triggers hearing loss a few days after the exposure to the sound. It also triggers this uncontrolled activity in the neurons of the dorsal cochlear nucleus. This is all happening very quickly, in a matter of days’
In a key breakthrough in collaboration with GSK who sponsored Dr Pilati’s PhD, the team also discovered the specific cellular mechanism that leads to the neurons’ over-activity. Malfunctions in specific potassium channels that help regulate the nerve cell’s electrical activity mean the neurons cannot return to an equilibrium resting state.
Ordinarily, these cells only fire regularly and therefore regularly return to a rest state. However, if the potassium channels are not working properly, the cells cannot return to a rest state and instead fire continuously in random bursts, creating the sensation of constant noise when none exists.
Dr Hamann explained: ‘In normal conditions the channel helps to drag down the cellular electrical activity to its resting state and this allows the cell to function with a regular pattern. After exposure to loud sound, the channel is functioning less and therefore the cell is constantly active, being unable to reach its resting state and displaying those irregular bursts.’
Although many researchers have investigated the mechanisms underlying tinnitus, this is the first time that cellular bursting activity has been characterised and linked to specific potassium channels. Identifying the potassium channels involved in the early stages of tinnitus opens up new possibilities for preventing tinnitus with early drug treatments.
Dr Hamann’s team is currently investigating potential drugs that could regulate the damaged cells, preventing their erratic firing and returning them to a resting state. If suitable drug compounds are discovered, they could be given to patients who have been exposed to loud noises to protect them against the onset of tinnitus. University of Leicester

Even mild head injuries can cause significant abnormalities in brain function that last for several days, which may explain the neurological symptoms experienced by some individuals who have experienced a head injury associated with sports, accidents or combat, according to a study by Virginia Commonwealth University School of Medicine researchers.
These findings advance research in the field of traumatic brain injury (TBI), enabling researchers to better understand what brain structural or functional changes underlie posttraumatic disorders – a question that until now has remained unclear.
Previous research has shown that even a mild case of TBI can result in long-lasting neurological issues that include slowing of cognitive processes, confusion, chronic headache, posttraumatic stress disorder and depression.
The VCU team, led by Kimberle M. Jacobs, Ph.D., associate professor in the Department of Anatomy and Neurobiology, demonstrated for the first time, using sophisticated bioimaging and electrophysiological approaches, that mild injury can cause structural disruption of axons in the brain while also changing the way the neurons fire in areas where they have not been structurally altered. Axons are nerve fibers in the brain responsible for conducting electrical impulses. The team used models of mild traumatic brain injury and followed morphologically identified neurons in live cortical slices.
‘These findings should help move the field forward by providing a unique bioimaging and electrophysiological approach to assess the evolving changes evoked by mild TBI and their potential therapeutic modulation,’ said co-investigator, John T. Povlishock, Ph.D., professor and chair of the VCU School of Medicine’s Department of Anatomy and Neurobiology and director of the Commonwealth Center for the Study of Brain Injury.
According to Povlishock, additional benefit may also derive from the use of this model system with repetitive injuries to determine if repeated insults exacerbate the observed abnormalities. Virginia Commonwealth University

Big gaps in basic knowledge about the numbers and causes of apparently inexplicable heart attacks among young sportsmen and women are seriously hampering our ability to prevent them, says a sport and exercise medicine specialist in the British Journal of Sports Medicine.
At the very least, we need to start building reliable databases of all such events across sport, in a bid to start plugging these knowledge gaps, say Dr Richard Weiler and colleagues.
His comments come in the wake of the recent high profile case of premier league footballer, Fabrice Muamba, who collapsed on pitch, in front of a stadium packed with spectators, after sustaining a sudden heart attack.
Fortunately, Mr Muamba recovered, but cases like these, although rare, are still likely to occur despite screening programmes, and they are poorly understood, emphasises Dr Weiler.
These cases have prompted improvements in pitch-side and acute sports medicine, including emergency life support, defibrillation and the development of practical education courses and emergency care guidelines, says Dr Weiler.
None the less, he says: ‘We still lack many answers to basic questions about these afflictions. We do not know the exact numbers and trends in prevalence or incidence, and do not understand the [multiple causes] that trigger sudden cardiac death in previously healthy athletes.’
Issues that still need further investigation are the roles of gender and ethnicity, geography and genes, he says.
For example, Sub-Saharan Africa may be a ‘cardiac hotspot,’ with recent research linking sudden heart attacks to sickle cell trait.
Other research suggests that African Americans are three times more prone to sudden cardiac death/arrest than white athletes, although the rates vary considerably depending on the type of sport played.
And another study found that heart (ECG) tracing patterns differ between white and black athletes, although whether this is normal or indicates a higher risk for sudden cardiac death is not known, says Dr Weiler.
Screening programmes throw up a considerable number of false positive results, and it is still far from clear whether screening actually cuts the number of deaths, whether it is cost effective, and how to manage any abnormal findings, he says.
‘It is vital that we start to answer these questions based on reliable science and evidence,’ he insists. ‘To achieve this, we propose the collection and recording of reliable data across sport of every sudden cardiac death/arrest,’ he writes.
But for this to happen, co-operation and collaboration will be needed among sporting organisations, federations, and clubs, in addition to the establishment of sport specific and national registries for these incidents, he suggests.
Dr Weiler cites a FIFA (International Football Federation) initiative. This requires a medical assessment before a match for all FIFA competitions, and includes a recently established database for all its 208 member associations in a bid to build up an evidence base and better understand the condition.
‘This is one of many efforts needed to fill knowledge gaps and enable us to mitigate the risks of sudden cardiac arrest/death,’ concludes Dr Weiler, adding that minimum standards of pitch-side medical care across all sports are essential. EurekAlert

Tufts Medical Center researchers have shown that presence of a gene strongly linked to appetite regulation is highly predictive of a premature infant’s readiness to feed orally. An analysis of just a drop of an infant’s saliva could be the key to preventing many feeding problems and the expensive medical complications that can occur when infants are fed by mouth too early.
In a study Maron and colleagues have identified a biomarker in saliva that predicts a baby is not yet ready to feed 95 percent of the time. The biomarker, a gene for the neuropeptide Y2 receptor, NPY2R, is a known regulator of feeding behaviour. In their study, the researchers demonstrated that levels of NPY2R in saliva decline as a newborn matures enough to feed orally.
‘There’s a really important need for a better understanding and a more accurate assessment of infants’ feeding skills, ” said Jill L. Maron, MD, MPH, a researcher at the Mother Infant Research Institute at Tufts Medical Center. ‘Nearly every baby born early is at risk for feeding associated morbidities, which often lead to prolonged hospitalisations, short and long term health complications, and significant parental anxiety. This is a way of monitoring the most vulnerable babies very non-invasively. We can help guide clinical care without ever hurting them.”
Currently, caregivers use a variety of subjective measurements, such as evaluating a baby’s sucking and swallowing skills, to determine when it’s safe to feed a baby by mouth. But these methods are imprecise and often lead to feeding a baby too early, which can cause the child to choke, accidentally inhale breast milk or formula into their lungs leading to pneumonia, or other problems. Babies who suffer these early feeding difficulties can also go on to develop long-term feeding problems and are at risk of developmental delays. Research indicates that more than 40 percent of children in feeding disorder clinics were premature babies.
The NPY2R gene has been studied extensively because it helps regulate appetite and plays a role in both obesity and eating disorders. But no one had examined its role in prompting premature babies to eat, because most researchers were not focusing on appetite’s role in newborn feeding problems. Tufts Medical Center